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(2025)Objective
Fremanezumab 225 mg monthly vs placebo — to evaluate efficacy and safety in adults with migraine and comorbid major depressive disorder over a 12-week double-blind period with 12-week open-label extension.
Study Summary
• HAM-D 17 depression score fell -6.0 vs -4.6 at week 8, a significant advantage for fremanezumab (p=0.02).
• More fremanezumab patients achieved ≥50% reduction in monthly migraine days at weeks 4, 8 and 12 (all p≤0.003).
• Benefits on migraine and depression were sustained through the 12-week open-label extension with quarterly 675 mg.
• Adverse events were consistent with prior fremanezumab trials; no new safety signals or deaths.
• First RCT designed specifically for migraine + comorbid MDD — supports CGRP mAb as a single agent for both conditions.
Intervention
Monthly subcutaneous fremanezumab 225 mg vs matched placebo for 12 weeks (double-blind), followed by 12-week open-label extension with quarterly fremanezumab 675 mg for all patients.
Inclusion Criteria
Adults 18-70 with episodic or chronic migraine (ICHD-3) for ≥12 months, onset ≤50 years, plus DSM-5 major depressive disorder for ≥12 months with active symptoms (PHQ-9 ≥10) at screening.
Study Design
Arms: Fremanezumab 225 mg monthly vs Placebo monthly
Patients per Arm: Fremanezumab 175; Placebo 178
Outcome
• HAM-D 17 change at week 8: fremanezumab -6.0 vs placebo -4.6; LSM diff -1.4 (95% CI -2.61 to -0.22); p=0.02
• ≥50% monthly migraine day reduction at week 12: 40% (70/176) fremanezumab vs 25% (44/177) placebo; p=0.002
• PHQ-9 score reduction larger with fremanezumab from week 8 onwards; benefits sustained in OLE (-6.9 monthly migraine days at week 24)
• Any AE 40% fremanezumab vs 27% placebo; serious AEs 1% vs <1%; AEs leading to discontinuation 2% vs 0
Clinical Question
In adults with migraine and comorbid major depressive disorder, does fremanezumab 225 mg monthly reduce monthly migraine days and depressive symptoms compared with placebo?
Bottom Line
In 353 adults with episodic or chronic migraine plus DSM-5 major depressive disorder (PHQ-9 ≥10), monthly fremanezumab 225 mg reduced monthly migraine days by -5.1 vs -2.9 with placebo over 12 weeks (p<0.001) and improved HAM-D 17 by -6.0 vs -4.6 at week 8 (p=0.02). First RCT specifically designed to test a CGRP mAb in comorbid migraine + MDD — supports fremanezumab as a single therapy targeting both conditions.
Major Points
- Multicenter double-blind placebo-controlled RCT at 55 centers in 12 countries, July 2020 - August 2022 (Lipton 2025)
- N=353 adults with EM (48%) or CM (52%) plus DSM-5 MDD for ≥12 months and PHQ-9 ≥10 at screening
- 1:1 randomization to monthly fremanezumab 225 mg or placebo for 12 weeks, then 12-week OLE with quarterly 675 mg fremanezumab for all
- Primary endpoint: mean change in monthly migraine days over 12-week double-blind period
- Fremanezumab reduced MMD by -5.1 vs -2.9 with placebo (p<0.001); least-squares mean difference -2.2 days
- HAM-D 17 depression score fell -6.0 vs -4.6 at week 8 (p=0.02); hierarchical testing failed after week 8 so downstream endpoints are nominal
- PHQ-9 favored fremanezumab from week 8; HIT-6 showed clinically meaningful improvement at week 12 in both groups (significance lost after hierarchy break)
- ≥50% MMD reduction rate at week 12: 40% fremanezumab vs 25% placebo (p=0.002)
- Benefits were sustained or numerically larger in OLE (overall MMD change -6.9 at week 24, HAM-D 17 change -8.0)
- Safety: any AE 40% vs 27%, serious AE 1% vs <1%, no deaths, no suicidality signals
- First RCT prospectively designed to test a CGRP mAb in patients with migraine + DSM-5 MDD — addresses a historically excluded population
- Supports fremanezumab as a single agent that may reduce disability and medication burden in comorbid migraine-depression patients
Study Design
- Study Type
- Phase 3 multicenter double-blind placebo-controlled parallel-group RCT (NCT04041284) with 12-week open-label extension
- Randomization
- Yes
- Blinding
- Double-blind for 12 weeks; open-label extension for next 12 weeks
- Sample Size
- 353
- Follow-up
- 28 weeks (4-week screening + 12-week double-blind + 12-week OLE)
Primary Outcome
Definition: Mean change from baseline in monthly migraine days over the 12-week double-blind period
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| -2.9 (95% CI -3.89 to -1.96) | -5.1 (95% CI -6.09 to -4.13) | - (Not explicitly reported for difference) | p<0.001 |
Limitations & Criticisms
- Hierarchical testing failed after week 8 HAM-D, so all downstream depression endpoints including PHQ-9 and HIT-6 are nominal rather than hierarchically confirmed
- Depression improvement could be partly indirect through migraine relief — trial design cannot fully disentangle mechanism
- Population was 97% White, 88% female — limits generalizability to racially/ethnically diverse populations
- COVID-19 pandemic overlapped the enrollment period; all COVID cases captured as AEs, potentially inflating AE rates
- Baseline HAM-D 17 (16.2) reflects moderate depression; effect in severe depression (PHQ-9 ≥20, 16% of cohort) not separately powered
- Monthly 225 mg dose only — no comparison with quarterly 675 mg in double-blind phase, limiting dose-response inference